Mycolate-specific T cell function in human immunity to Mycobacterium tuberculosis Mycolic acids are abundant constituents of the mycobacterial cell wall whose hydrophobicity leads to the clinically-useful acid-fast smear. Mycolic acid synthesis is the target of the potent anti-mycobacterial agent Isoniazid. Whereas T cells were previously thought to solely recognize peptide antigens, CD1b-restricted human T cells recognize mycolates in vitro, raising the possibility that lipid-reactive T cells influence outcomes in human infection with Mycobacterium tuberculosis. The applicant has developed and validated CD1b tetramers for tracking lipid reactive T cells at the single cell level ex vivo and within tissues. As part of a five-year training program in the laboratory of Branch Moody MD, the applicant will use CD1b tetramers to study mycolate-specific T cells from tuberculosis patients. T cells from a small number of subjects will be analyzed in detail in order to determine CD1b-restricted, mycolate-specific T cell lineage, anti-mycobacterial properties and potential for mediating memory responses (Aim 1). Subsequent cross-sectional study of human populations with latent or active tuberculosis will allow correlation of mycolate-specific T cell frequency with prior exposure to Mycobacterium tuberculosis (Aim 2A). Functional memory of mycolate- specific T cells as measured by persistence over one year of infection will be measured retrospectively in collaboration with investigators at the KwaZulu Natal Research Institute for TB and HIV in South Africa (Aim 2B). Finally, isolation of mycolate-specific T cells from human tissues with latent or active TB infection will allow their measurement in tissues at the site of disease (Aim 2C). The low level of polymorphism of CD1b genes in comparison to MHC as well as the relative resistance of lipid biosynthetic pathways to immune selection pressure make mycolate-specific T cells attractive molecular targets for immunomodulation or vaccination. This project serves as a career development award for Dr. Kasmar whose objective is to become an investigator of human immunity to infection. Tuberculosis is an infectious disease which is transmitted by coughing. Millions of people get sick from tuberculosis every year and many die. We are studying human T cells specific for TB-lipids in order to develop new diagnostic tests and vaccines.